PROJECT SUMMARY Gammaherpesviruses infection is characterized by lifelong persistence in the host cells by entering quiescent period known as latent infection. During latency, only limited set of genes is expressed that include genome maintenance proteins LANA for KSHV and EBNA1 for EBV. Both LANA and EBNA1 have been linked to cellular transformation although the underlying mechanism is still unclear. In this proposal, we will investigate this oncogenesis mechanism of latent gammaherpesviruses. Our earlier study has recognized that one of EBV kinases, BGLF4, interacts with TIP60 protein in the host cells to regulate viral lytic replication. TIP60 is a cellular acetyltransferase that plays important roles in gene transcription, cell apoptosis, and DNA damage response. The role of TIP60 as a tumor suppressor has been established in vivo in mouse model and in human tumors. We recently demonstrated that TIP60 was required for KSHV lytic replication as well, indicating its broad herpesviruses role. Interestingly, we also found that TIP60 interacted with LANA and EBNA1 during latency that correlated with significant reduction of TIP60?s histone acetyltransferase activity. These results lead us to our hypothesis that latent gammaherpesviruses temporally regulate acetyltransferase activities of TIP60 as the critical mechanism in cancer development. Our specific aims to study this hypothesis are: (i) to first investigate the mechanism and impact of TIP60 inhibition in gammaherpesviruses latency (ii) and to characterize anti-tumor activities of TIP60 in gammaherpesviruses-infected lymphoma. Outcome from these investigations will identify the unique molecular features of gammaherpesviruses-related tumors that can explain why latent gammaherpesviruses are oncogenic. It will also provide the basis for future studies on development of therapeutic strategy for AIDS-related lymphoma.